PROJECTSUMMARY Mycobacterium tuberculosis (Mtb)?the causative agent of the disease tuberculosis (TB)? has afflicted humans for thousands of years. It is the leading worldwide bacterial cause of death. Treatment requires multiple antibiotics for at least six months. In addition, there is rising prevalence of extensively drug resistant isolates, and the pipeline for new anti-mycobacterials is inadequate. Mtb?s success rests upon the fact that it grows in macrophages. This raises the possibility that host-directed therapeutics (HDTs) in combination with antibacterials might shorten treatment courses or reduce immunopathology. Here, we investigate whether drugs that block host fatty acid b?-oxidation (FAO) can treat TB. This proposal is based upon our unexpected discoverythatFAOinhibitors,includingtrimetazidinewhichisapprovedforclinicaluse,blocktheintracellular growthofMtb.WehypothesizethatFAOinhibitorspreventMtbfromgrowingwithinmacrophagesbyinducing cellular oxidative stress, activating autophagy, and promoting pro-inflammatory cytokine production. We will investigatetheanti-mycobacterialactivityofthesecompounds,definetheirantimicrobialmechanismofaction, andevaluatetheiranti-tuberculousefficacyinvivo.OurproposedstudieswillestablishwhetherFAOisahost pathwaytotargetforTBtreatment.Inaddition,thesestudieswillcontributetoourbasicunderstandingofMtb pathogenesis. Given the favorable pharmacokinetics and safety profiles of FAO inhibitors, our findings could rapidlytranslatetopatientswithmulti-drugresistant(MDR)TB.